1. Field of the Invention
The present invention relates to a novel ellipticine derivative having a strong antineoplastic or antitumor activity and, also, relates to a production process thereof.
2. Description of the Related Art
Pyridocarbazole alkaloids such as ellipticine, i.e., 5, 11-dimethyl-6H-pryrido [4,3-b] carbazole (i.e., R=H in the following general formula (A)), and 9 -methoxyellipticine (i.e., R=OCH.sub.3 in the following general formula (A)) are known as alkaloids contained in, for example, Aspidospermina and Ochrosia leaves. ##STR2##
Recently, it was reported in J. Rouess'e et. al, Bull. Cancer (Paris), 68, 437-441 (1981) that 2-methyl-9-hydroxyelliptiscinium acetate (Celiptium) having the general formula (B): ##STR3## is effective against mammary cancer. It was also reported, in R.W. Guthrie et. al, J. Medicinal Chemistry, 18 (7), 755-760 (1975), that elipticine and 9-methoxyellipticine are effective against the tumor of animals used for experiments, mouse lymphoid leukemia L-1210 and Sarcoma 180 (solid) and, in Japanese Examined Patent Publication (Kokoku) No. 58-35196 and British Pat. No. 1436080, that the activity of 9-hydroxyellipticine against mouse lymphoid leukemia L-1210 is higher, by more than 100 to 1000 fold, than that of 9-methoxyellipticine.
As mentioned above, compounds having a pyridocarbazole skeleton are useful because they have an antineoplastic or antitumor activity. Various studies or research to synthesize those compounds have been reported in, for example, L.K. Dalton et. al., Aust. J. Chem., 20, 2715-2727 (1967); A.H. Jackson et. al., J. Chem. Soc. Perkin I, 1698-1704 (1977); J.Y. Lallemand et. al, Tetrahedron Letters, No. 15, 1261-1264 (1978); and European Patent Specification No. 9445. Furthermore, it is disclosed in U.S. Pat. No. 4,434,290 that compounds having certain substituents introduced into the pyridocarbazole skeleton have an activity against mouse lymphoid leukemia L-1210.
However, ellipticine, 9-methoxyellipticine, and 9-hydroxyellipticine have not been clinically used yet as an antineoplastic or antitumor agent. This is because, among other reasons, the water-solubilities of these compounds are very poor. Although Japanese Unexamined Patent Publication (Kokai) No. 58-222087 proposes the oxidation of 2-alkyl-9-hydroxyellipticinium salts to introduce amino acids, oligopeptides, nucleotides, or nucleosides into the 10-position of the skeleton. However, these compounds do not provide desirable life-prolongation effects against mouse lymphoid leukemia L-1210.